Schematic showing DPM1 regulates DSP expression on the cell membrane through SERPINB5, which can directly interact with DSP in keratinocytes, and this interaction is dependent on EGFR activity. DPM1 loss has functional consequences on cell–cell adhesion, cytoskeletal organization, and epidermal differentiation, which can be partly restored by rescue of SERPINB5 expression. Further, DSP localization on the surface is negatively regulated by phosphorylation of DSP on the S176 position, which is significantly enhanced in DPM1 KD cells, and interestingly SERPINB5 rescues the phosphorylation of DSP at S176 in DPM1 KD background.